tbuckley/cabot-search huggingface dataset:
Neoadjuvant versus adjuvant chemotherapy for resectable metastatic colon cancer in non-academic and academic programs.
Authors: Zhonglin Hao, Saurabh Parasramka, Quan Chen, Aasems Jacob, Bin Huang
Journal: Journal of Clinical Oncology (2022)

e15607 Background: Approximately 21% of colon cancer patients have synchronous metastatic disease at presentation. Liver is by far the most common site of metastasis. For resectable and borderline resectable metastatic lesions after conversion to surgical resection, five-year survival ranges between 40-70%. Overall survival advantage of chemotherapy before and after metastasectomy of liver or lung lesion is not clear. We here compare the differential effect of neoadjuvant versus adjuvant chemotherapy on overall survival of patients who received resection of both primary and metastatic lesions in non-academic and academic settings from the National Cancer Database (NCDB). Methods: Adults 20 years or older with primary colon cancer and single organ metastatic disease either in the liver or lung at diagnosis between 2010-2015 were identified. All patients had received surgery to the primary site, resection of the distant site and chemotherapy within 1 year of diagnosis. Patients were categorized into 2 cohorts based on whether they received chemotherapy in the pre-operative/peri-operative setting (neoadjuvant chemotherapy –NAC) or post-operative setting (adjuvant chemotherapy AC). Descriptive analysis, Kaplan-Meier plots, Log-Rank tests, and Cox-regression models for multivariate survival analyses were performed. To assess uncertainty of estimates, a sensitivity analysis was also performed based on the intention to treat principle by including additional surgery only and chemotherapy only cases. Results: A total of 3,038 colon cancer patients with liver or lung metastases were identified between 2010-2015. A larger majority of patients (n = 2387, 78.6%) received AC. The percentage of patients receiving NAC had steadily increased from 2010-2015 from 12.29% to 28.31%. The supermajority of metastases was in the liver. On multivariate analysis, patients who received NAC had an overall survival advantage (HR 0.661; 95% CI 0.534-0.879; P = 0.0001) in the non-academic setting whereas no advantage is seen in the patients treated in the academic settings (HR 0.994; 95% CI 0.831-1.189; P &lt; 0.9484). The median overall survival for patients receiving NAC and AC was 47.24 months and 38.08 months respectively. Clinical factors associated with overall survival advantages in NAC patients treated in non-academic programs included age 20-49 years; low-income (&lt; $38,000/year) status; CEA value of &gt; 30; right sided colon primary; low T status and liver metastasis among others. The survival advantage of NAC over AC is associated with more clean resection margin and fewer regional lymph node involvement after surgery. Conclusions: Metastatic colon cancer with single organ liver or lung lesions benefits from neoadjuvant chemotherapy especially in non-academic settings based on our analysis of the NCDB database. The overall survival advantage in this setting has not been shown before.
Development of heterobifunctional proteomimetic polymers for delivery of MYC inhibitory peptides and targeted MYC degradation.
Authors: Mihai Ioan Truica, Max Mu Wang, Brayley Gattis, Sarki Abdulkadir, Nathan Gianneschi
Journal: Journal of Clinical Oncology (2022)

e15049 Background: The c-Myc(Myc) oncogene plays critical roles in tumorigenesis and therapeutic resistance, being dysregulated in up to 70% of all human cancers. Heterodimerization with the closely related bHLH-LZ protein Max is required for oncogenic transformation, yet the development of small molecule inhibitors has been challenging since disordered Myc and Max monomers lack suitable binding pockets, while the Myc-Max interface is flat and extensive. Myc inhibitory peptides derived from the first helix (H1) of the bHLH-LZ region have overcome the limited binding affinity of small molecules. However, poor cellular penetrance and extremely limited bioavailability have precluded clinical translation of peptide-based approaches. Aim: To address and improve the limitations and low potential for clinical translation of Myc inhibitory peptides via a versatile peptide delivery platform. This novel platform technology is referred to as the Protein-Like Polymer (PLP) and it is based on packaging peptides together as high-density brush polymers. Methods: We generated H1-PLPs using ring-opening metathesis polymerization and characterized them using HPLC, LC-MS, NMR, and GPC. We also explored the potential of PLPs to be designed as heterobifunctional compounds by copolymerizing with secondary side chain peptides (nuclear localization sequences and degron sequence). For biological studies, immunofluorescence and confocal microscopy were used to assess cellular penetration; cellular viability assays coupled with use of both cellular (isogenic pairs, Myc-dependent and independent lines) and biochemical (scrambled H1 sequence, homopolymers, monomeric peptides) controls were used to assess tumor antiproliferative effects and Myc-based selectivity of response. Myc target engagement was assessed via immunoprecipitation assays and dual-reporter luciferase-based assays. Results: Our studies show that heterobifunctional PLPs employing H1 peptide and a degron sequence are cell-penetrating and co-localize with Myc in the nucleus. They display antiproliferative effects with submicromolar IC50 values in a Myc-dependent manner. The PLPs lead to Myc/Max complex disruption, promote significant levels of Myc degradation and prevent binding of Myc/Max heterodimers to the Myc/Max consensus canonical DNA binding site. Selectivity studies reveal that antiproliferative effects are dependent on intact H1 sequence. Animal studies using transplanted Myc-CaP model, which mimics the clinical course of human castration resistant prostate cancer are ongoing. Conclusions: We present a novel peptide delivery platform that addresses the challenges inherent to peptide delivery approaches. The presented work demonstrates the feasibility of this platform in delivering Myc inhibitory peptides and provides rationale for further in vivo studies in Myc-dependent tumor models.
Validity and efficiency of progression-free survival (PFS)-2 as a surrogate endpoint for overall survival (OS) in advanced cancer.
Authors: Rachel Woodford, Deborah Zhou, Peey-Sei Kok, Sally Lord, Michael Friedlander, Ian Marschner, John Simes, Chee Khoon Lee
Journal: Journal of Clinical Oncology (2022)

6518 Background: PFS is used widely as a primary endpoint in oncology trials and as a surrogate for OS. PFS-2, defined as time from randomization to progression on second line therapy, is potentially a more reliable surrogate than PFS but requires additional follow-up time. We evaluated the validity and efficiency of PFS-2 as a surrogate endpoint for OS and compared its performance with PFS. Methods: We performed an electronic search to identify randomized trials of advanced solid tumors reporting on PFS, PFS-2 and OS as pre-specified endpoints. We compared the correlations in the relative treatment effect for OS with PFS and PFS-2. We extracted data from Kaplan-Meier survival curves to create individual patient data to estimate time to statistical significance (TSS), defined as logrank P &lt; 0.05. We further computed the samples size (person-year follow-up) required to reach statistical significance and assessed for the effect of survival post-progression (SPP). If trials failed to reach statistical significance for a particular endpoint, the maximal follow-up time was used. Results: Our study consisted of 39 analysis units with 20714 patients. Correlations of the OS treatment effect with the PFS and PFS-2 treatment effects were r= 0.12 (95% CI 0.00-0.13) and r= 0.67 (95% CI 0.08-0.69) respectively. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS2 with PFS were 8.7, 8.4, and 3.2 months respectively. For trials with a SPP &lt; 12 months, smaller differences in the median TSS as compared to SPP ≥12 months were seen. The median differences in follow-up required to reach statistical significance were 329, 151 and 122 person-years (PY) respectively. These differences were equivalent to a median 18.3% increase in sample size required for PFS-2 over PFS. The median increase in sample sizes were 18.2% and 22.3% for trials with SPP &lt; 12 and ≥12 months respectively. Conclusions: PFS-2 has a stronger correlation with OS benefit than PFS. When PFS-2 is used as primary endpoint, trials will require an additional median 3.2 months to achieve statistical significance, and an additional 18.3% increase of sample size over PFS. PFS-2 balances between improved correlation with OS but modest increase in follow-up time and sample size. PFS-2 should therefore be considered as a primary endpoint in future trials of advanced cancers.[Table: see text]
Clinical N3 as an independent risk factor of recurrence for breast cancer patients achieving pathological complete response and near-pathological complete response after neoadjuvant chemotherapy.
Authors: Xiaoyan Qian, Pin Zhang, Meng Xiu, Qing Li, Jiayu Wang, Ying Fan, Yang Luo, Ruigang Cai, Qiao Li, Peng Yuan, Fei Ma, Binghe Xu
Journal: Journal of Clinical Oncology (2022)

e12619 Background: Although achieving pathological complete response (pCR) and near-pathological complete response (near-pCR) after neoadjuvant chemotherapy (NAC) in breast cancer predicts a better outcome, some patients still experience recurrence. The aim of our study was to analyse the predictive factors of recurrence in the pCR and near-pCR population. Methods: We reviewed 1209 breast cancer patients treated with NAC. A total of 292 patients achieving pCR and near-pCR between January 2010 and April 2021 in the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) were included in our analysis. pCR was defined as ypT0N0/ypTisN0. Near-pCR was defined as ypT1mi/1a/1bN0 or ypT0/isN1mi. The Kaplan-Meier method with the log rank test was used to estimate recurrence analysis. Results: Of the 292 patients,173 were pCR and 119 were near-pCR. The median age was 46 years (range 23-75 years). The predominant tumor subtype was human epidermal growth factor receptor type 2 (HER2) positive (49.0%) and triple-negative breast cancer (TNBC) (30.8%). The median duration of follow-up was 53 months (range 9-138 months). A total of 16 (8.9%) patients developed recurrence, with 9 (5.2%) in the pCR group and 16 (13.4%) in the near-pCR group. The vast majority of recurrence occurred within 36 months from onset of NAC. The 5-year recurrence-free survival (RFS) rate of patients achieving pCR was significantly higher than that of patients achieving near-pCR (94.6% vs.85.6%, P=0.008). Clinical N3 (cN3) before NAC was an independent factor of higher risk for recurrence in patients who achieved pCR ( P=0.003) and near-pCR ( P=0.036). Tumor size before NAC, subtype of breast cancer and chemotherapy regimens showed no significant association with RFS both for patients who achieved pCR and near-pCR ( P ≥0.05). Conclusions: cN3 before NAC was an independent factor of higher risk for recurrence in patients who achieved pCR and near-pCR. It is worthwhile to monitor closely for patients with cN3, especially in the first 3 years.
New strategies for multimodal analgesia in patients with high-risk geriatric cancer in perioperative period.
Authors: Sergey V. Tumanyan, Dmitry A. Rozenko, Oksana V. Oros, Aleksandr V. Shepelenko, Svetlana A. Chekmezova, Natalia N. Popova
Journal: Journal of Clinical Oncology (2022)

12046 Background: Perioperative pain (POP) in high-risk geriatric patients with cancer (HRGCP) is an important issue. The purpose of this study was to optimize perioperative analgesia in HRGCP. Methods: This randomized study of the quality and effectiveness of perioperative analgesics included 115 HRGCP aged 64-88 years who underwent surgeries on the organs of the chest, abdomen and pelvis for various cancers. The patients were divided into 2 groups. Group 1 (n = 52): patient-controlled analgesia with morphine and nonsteroidal anti-inflammatory drugs (NSAIDs); group 2 (n = 63): ultrasound-guided bilateral transversus abdominis plane (TAP) block with ropivacaine. Intraoperative and perioperative analgesia was maintained with a continuous infusion of lidocaine, magnesium sulphate, microdoses of fentanyl and NSAIDs. Results and pain syndrome were assessed by monitoring the Efficacy Safety Score (ESS), personal and reactive anxiety, stress response (cortisol, insulin, lactate, glucose), rates of functional activity recovery, the need for opioid analgesics, frequency of postoperative nausea and vomiting (PONV). Results: Patients in group 2 showed a significant decrease in the perioperative need for opioid analgesics and significantly decreased POP. Analysis of variance of mean values revealed statistically lower scores of ESS, visual analogue scale and POP (p &lt; 0.05) during the first 24 hours of perioperative period in group 2 compared with group 1. Patient-controlled analgesia showed analgesic effect in 88.5% (p &lt; 0.05) cases. However, the effect was less pronounced, compared to multimodal analgesia, and did not reduce cognitive disorders. In group 2, opioid-sparing analgesic effect was 95.3% (p &lt; 0.05). Multimodal analgesia reduced the stress response (p &lt; 0.05) in perioperative period and did not cause cognitive dysfunction while reducing PONV episodes, unlike morphine. Despite the minimal doses of narcotic analgesics in group 2, multimodal analgesia provided safe analgesia and functional activity recovery in perioperative period with minimum negative effects of opioids. Conclusions: The strategy of multimodal analgesia based on a combination of intraoperative TAP block and infusions of lidocaine and microdoses of fentanyl can significantly improve the quality of analgesia in perioperative period.
Prevalence of frailty for middle-aged and older adults starting a new line of systemic cancer treatment: Is age just a number?
Authors: Mackenzi Pergolotti, Kelley C Wood, Mary Hidde, Tiffany Kendig, Grant Richard Williams, Smith Giri, Ellen A. Ronnen, Rachel Carroll
Journal: Journal of Clinical Oncology (2022)

12054 Background: Frailty is associated with adverse outcomes and increased risk of mortality for older adults (&gt;60 years) with cancer. Geriatric assessment (GA) has gained popularity in routine cancer care as a clinical tool to screen for frailty in older adults starting a new line of cancer treatment, and to guide clinical decision making during systemic therapy. Emerging research indicates GA may also be useful to identify frailty in middle-aged adults (40-60 years) with cancer, but more research is needed. In this study, we used GA data to compare the prevalence of frailty between middle-aged and older adults starting a new line of systemic cancer treatment. Methods: Participants included adult patients with cancer due to begin a new line of systemic therapy at a multi-office community-based oncology private practice and enrolled in a clinical trial (NCT04852575). At baseline, participants completed an online version of the Cancer and Aging Resilience Evaluation (CARE) — a patient-reported GA adapted from the Cancer and Aging Research Group. Frailty score was constructed using a 44-item deficit accumulation method and categorized as frail (&gt;0.35), pre-frail (0.2-0.35) or robust (0-0.2) using published cutoffs. We grouped participants by age, middle-aged (40-60 years) or older-aged (&gt;60 years), then used independent t-test and chi-squared statistic to compare frailty scores (continuous) prevalence of frailty (categorical) between groups. Hypothesis testing was two sided and the level of significance was 0.05. Results: Participants ( n=96) were predominantly female (62%), Caucasian (68%) and beginning first line systemic therapy (69%) for either newly diagnosed cancer or new recurrence of disease; median time since diagnosis was 1 month. Common cancer types included: breast (34%), gastrointestinal (23%), hematologic (15%) and lung (12%). Disease stage was predominantly stage 3 (28%) or stage 4 (38%). When comparing middle-aged ( n=31, M age = 54.74 ± 4.79, range = 41.23 – 59.98 years) vs. older adult -groups ( n=65, M age = 70.27 ± 5.91, range = 60.64 – 84.29 years), there was no significant difference in mean frailty score ( p = 0.22) or the proportion categorized as frail vs. pre-frail vs. robust ( p = 0.32); see Table. Stage of disease and prevalence of common cancer types was similar between age groups (p&gt;.05). Conclusions: In our cohort, middle and older aged patients who completed patient-report GA had similar prevalence of frailty before starting systemic therapy. Using the GA as a functional-age assessment to detect frailty for adults of varied ages could allow for earlier intervention aimed at impacting tolerance to therapy. Clinical trial information: NCT04852575. [Table: see text]
Participation in cancer research in BNSSG, England: A Health Equity Audit 2021.
Authors: Kathryn Hamilton, Helen Winter, Diana Benton, Helen Lewis-White, Owen Ainsley, Emily Eyles
Journal: Journal of Clinical Oncology (2022)

1565 Background: Cancer is a cause of health inequalities, and nationally, patients from deprived communities have lower participation rates in cancer research. Equitable access to research benefits patients, healthcare organisations and improves applicability of research. Methods: We undertook a health equity audit of participation in cancer research (trials and non-trials based) in Bristol, North Somerset and South Gloucestershire (BNSSG), England from 1.4.2019-30.3.2020 using data from the Acute Trust patient datasets. Comparison cohorts were extracted from a regional primary care dataset (the system wide dataset). Firstly, an incident cancer cohort: diagnosed from 1.11.2019-1.10.2020. Secondly a “living with cancer” cohort: cancer flag in the 5 years prior to 1.7.2021. Deprivation is measured by IMD of home postcode small area (LSOA). Results: Results are presented for the audit in the table below, with 95% confidence intervals where appropriate. Compared to people newly diagnosed with cancer, adults aged 70 or older were 56% less likely to take part in research (OR 0.44, 95% CI 0.39-0.51), and adults aged 80 or older were 77% less likely to take part in research (OR 0.23, 95% CI 0.18-0.29). Compared to people newly diagnosed with cancer, people from the most deprived 20% of the population were 27% less likely to take part in research (OR 0.73, 95% CI 0.88-0.92). The most deprived research participants were more likely to be younger, have one or more comorbidities and a recent emergency admission. Patients from outside BNSSG (18%) appear similar in profile to those from within BNSSG, including for deprivation. Better data are needed for other factors relevant to equity, including ethnicity and Inclusion Health. Conclusions: This health equity audit confirms and quantifies inequities in access to cancer research in our region. Under-representation of deprived and older patients appeared multifactorial in this audit, but further work to understand facilitators and barriers to recruitment is needed. These results are a call to action. [Table: see text]
Serum liquid metabolites reveals the heterogeneity in advanced lung adenocarcinoma patients with EGFR sensitizing mutations.
Authors: Xinyang Du, Hua Bai, Jie Wang
Journal: Journal of Clinical Oncology (2022)

e21065 Background: There is a differential therapeutic efficacy of advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). This study aimed to explore the differences in serum liquid metabolites of EGFR mutation types and to provide further evidence for revealing the mechanism of the difference in efficacy. Methods: In total, 42 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received EGFR-TKIs therapy were included. Prospectively collected serum samples before initial treatment were utilized to perform nontargeted liquid metabolomics profiling analyses under the application of Ultrahigh Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS). Multi-dimensional statistical methods such as partial least squares discrimination analysis (PLS-DA) were used to further screen and identify differential metabolites associated with EGFR mutation type. Results: The metabolic signature molecules in the metabolic profile were extracted, and a total of 1995 positive ion mode (ESI+) and 365 negative ion mode (ESI-) signature molecules were obtained. 29 metabolites displayed significant differences between the two groups, which belong to lipids including phosphatidylcholines (PCs), phosphatidylglycerol (PGs), phosphatidylethanolamine (PEs), ceramides (Cers) and sphingomyelins (SMs). Gene mutation subtypes change the proportion of saturated phospholipids and unsaturated phospholipids, with significantly higher saturated phospholipids in patients with the EGFR 21 L858R mutation. Then, pathway enrichment analysis was performed on the differential metabolites, mainly enriched in glycerophospholipid and sphingolipids metabolism pathway. Conclusions: This study not only demonstrates the heterogeneity of lipid metabolism among gene mutation subtypes, but also provides the possibility to reveal the mechanism of survival differences.